This invention is concerned with a new intermediate and process for preparing 17.beta.-acylsubstituted 3-oxo-4-azasteroids by utilizing a 17.beta.-N-methoxy-N-methyl carboxamide as a common intermediate.
Processes for making 17.beta.-acyl-substituted 3-oxo-4-azasteroids are known in the art. For example, European Patent Application 85301122.9 discusses the synthesis of 17.beta.-acyl-substituted 3-oxo-4-azasteroids involving the formation of a 17.beta.-(2-pyridylthiocarbonyl)-3-oxo-4-aza steroid which can be substituted at the 4-position and can have a double bond at the 1,2-positions. This compound is then reacted with a Grignard reagent to form a 17.beta.-acyl-3-oxo-4-aza steroid. While this process is practical for small scale preparations, it has the disadvantage of requiring extensive chromatography to obtain the final product.
Rasmusson et. al., J. Med. Chem. 1986, 29, 2298-2315 and U.S. Pat. Nos. 4,220,775 and 4,377,584 also discuss the synthesis of 17.beta.-substituted 3-oxo-4-azasteroids involving the use of a very reactive 17.beta.-imidazolide intermediate in a Grignard reaction. Extensive chromatography is also required here.
Other methods are known for producing 17.beta.-acyl androstenones and involve reacting a 17.beta.-carboxylic acid ester with Grignard reagents, e.g. phenylmagnesium bromide to form the 17.beta.-acyl analog. However, a serious side reaction occurs wherein the product 17.beta.-acyl compound formed by the Grignard Reaction, can undergo further reaction with the Grignard reagent to produce the diphenyl carbinol, e.g., see Compound 4 in Scheme 1, compromising yield and purity of the desired ketone.
What is desired in the art is an 17.beta.-substituted androstenone intermediate which is stable and which can undergo reaction with a Grignard reagent to produce 17.beta.-acyl androstenones in high yield and purity.